tbuckley/cabot-search huggingface dataset:
A Phylogenomic Assessment of Processes Underpinning Convergent Evolution in Open-Habitat Chats
Authors: Niloofar Alaei Kakhki, Manuel Schweizer, Dave Lutgen, Rauri C K Bowie, Hadoram Shirihai, Alexander Suh, Holger Schielzeth, Reto Burri
Journal: Molecular Biology and Evolution (2022)

Insights into the processes underpinning convergent evolution advance our understanding of the contributions of ancestral, introgressed, and novel genetic variation to phenotypic evolution. Phylogenomic analyses characterizing genome-wide gene tree heterogeneity can provide first clues about the extent of ILS and of introgression and thereby into the potential of these processes or (in their absence) the need to invoke novel mutations to underpin convergent evolution. Here, we were interested in understanding the processes involved in convergent evolution in open-habitat chats (wheatears of the genus Oenanthe and their relatives). To this end, based on whole-genome resequencing data from 50 taxa of 44 species, we established the species tree, characterized gene tree heterogeneity, and investigated the footprints of ILS and introgression within the latter. The species tree corroborates the pattern of abundant convergent evolution, especially in wheatears. The high levels of gene tree heterogeneity in wheatears are explained by ILS alone only for 30% of internal branches. For multiple branches with high gene tree heterogeneity, D-statistics and phylogenetic networks identified footprints of introgression. Finally, long branches without extensive ILS between clades sporting similar phenotypes provide suggestive evidence for the role of novel mutations in the evolution of these phenotypes. Together, our results suggest that convergent evolution in open-habitat chats involved diverse processes and highlight that phenotypic diversification is often complex and best depicted as a network of interacting lineages.
How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia
Authors: Noam E. Kopmar, Ryan D. Cassaday
Journal: Blood (2022)

The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.
Case 39-2022: A 31-Year-Old Woman with Postpartum Abdominal Pain and Fever
Authors: Sarah E. Little, Onofrio A. Catalano, Andrea G. Edlow, Stuti G. Shroff
Journal: New England Journal of Medicine (2022)

A 31-year-old woman was admitted 15 days after the birth of her child because of abdominal pain and fever. She had mild tenderness in the left upper quadrant and at the left costovertebral angle. A diagnosis was made.
Association of Patient Risk Factors, Tumor Characteristics, and Treatment Modality With Poor Outcomes in Primary Cutaneous Squamous Cell Carcinoma
Authors: George A. Zakhem, Akshay N. Pulavarty, John Carucci, Mary L. Stevenson
Journal: JAMA Dermatology (2022)

Primary cutaneous squamous cell carcinoma is usually curable; however, a subset of patients develops poor outcomes, including local recurrence, nodal metastasis, distant metastasis, and disease-specific death.To evaluate all evidence-based reports of patient risk factors and tumor characteristics associated with poor outcomes in primary cutaneous squamous cell carcinoma and to identify treatment modalities that minimize poor outcomes.PubMed, Embase, and SCOPUS databases were searched for studies of the topic in humans, published in the English language, from database inception through February 8, 2022.Two authors independently screened the identified articles and included those that were original research with a sample size of 10 patients or more and that assessed risk factors and/or treatment modalities associated with poor outcomes among patients with primary cutaneous squamous cell carcinoma.Data extraction was performed by a single author, per international guidelines. The search terms, study objectives, and protocol methods were defined before study initiation. A total of 310 studies were included for full-text assessment. Owing to heterogeneity of the included studies, a random-effects model was used. Data analyses were performed from May 25 to September 15, 2022.For studies of risk factors, risk ratios and incidence proportions; and for treatment studies, incidence proportions.In all, 129 studies and a total of 137 449 patients with primary cutaneous squamous cell carcinoma and 126 553 tumors were included in the meta-analysis. Several patient risk factors and tumor characteristics were associated with local recurrence, nodal metastasis, distant metastasis, disease-specific death, and all-cause death were identified. Among all factors reported by more than 1 study, the highest risks for local recurrence and disease-specific death were associated with tumor invasion beyond subcutaneous fat (risk ratio, 9.1 [95% CI, 2.8-29.2] and 10.4 [95% CI, 3.0- 36.3], respectively), and the highest risk of any metastasis was associated with perineural invasion (risk ratio, 5.0; 95% CI, 2.3-11.1). Patients who received Mohs micrographic surgery had the lowest incidence of nearly all poor outcomes; however, in some results, the 95% CIs overlapped with those of other treatment modalities.This meta-analysis identified the prognostic value of several risk factors and the effectiveness of the available treatment modalities. These findings carry important implications for the prognostication, workup, treatment, and follow-up of patients with primary cutaneous squamous cell carcinoma.PROSPERO Identifier: CRD42022311250.
Can <i>The Matrix</i> Help Treat Recurrent Hepatocellular Carcinoma?
Authors: Harufumi Maki, Anish J. Jain, Jean-Nicolas Vauthey
Journal: JAMA Surgery (2022)

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Predictive Utility of a Coronary Artery Disease Polygenic Risk Score in Primary Prevention
Authors: Nicholas A. Marston, James P. Pirruccello, Giorgio E. M. Melloni, Satoshi Koyama, Frederick K. Kamanu, Lu-Chen Weng, Carolina Roselli, Yoichiro Kamatani, Issei Komuro, Krishna G. Aragam, Adam S. Butterworth, Kaoru Ito, Steve A. Lubitz, Patrick T. Ellinor, Marc S. Sabatine, Christian T. Ruff
Journal: JAMA Cardiology (2022)

The clinical utility of polygenic risk scores (PRS) for coronary artery disease (CAD) has not yet been established.To investigate the ability of a CAD PRS to potentially guide statin initiation in primary prevention after accounting for age and clinical risk.This was a longitudinal cohort study with enrollment starting on January 1, 2006, and ending on December 31, 2010, with data updated to mid-2021, using data from the UK Biobank, a long-term population study of UK citizens. A replication analysis was performed in Biobank Japan. The analysis included all patients without a history of CAD and who were not taking lipid-lowering therapy. Data were analyzed from January 1 to June 30, 2022.Polygenic risk for CAD was defined as low (bottom 20%), intermediate, and high (top 20%) using a CAD PRS including 241 genome-wide significant single-nucleotide variations (SNVs). The pooled cohort equations were used to estimate 10-year atherosclerotic cardiovascular disease (ASCVD) risk and classify individuals as low (<5%), borderline (5-<7.5%), intermediate (7.5-<20%), or high risk (≥20%).Myocardial infarction (MI) and ASCVD events (defined as incident clinical CAD [including MI], stroke, or CV death).A total of 330 201 patients (median [IQR] age, 57 [40-74] years; 189 107 female individuals [57%]) were included from the UK Biobank. Over the 10-year follow-up, 4454 individuals had an MI. The CAD PRS was significantly associated with the risk of MI in all age groups but had significantly stronger risk prediction at younger ages (age <50 years: hazard ratio [HR] per 1 SD of PRS, 1.72; 95% CI, 1.56-1.89; age 50-60 years: HR, 1.46; 95% CI, 1.38-1.53; age >60 years: HR, 1.42; 95% CI, 1.37-1.48; P for interaction <.001). In patients younger than 50 years, those with high PRS had a 3- to 4-fold increased associated risk of MI compared with those in the low PRS category. A significant interaction between CAD PRS and age was replicated in Biobank Japan. When CAD PRS testing was added to the clinical ASCVD risk score in individuals younger than 50 years, 591 of 4373 patients (20%) with borderline risk were risk stratified into intermediate risk, warranting initiation of statin therapy and 3198 of 7477 patients (20%) with both borderline or intermediate risk were stratified as low risk, thus not warranting therapy.Results of this cohort study suggest that the predictive ability of a CAD PRS was greater in younger individuals and can be used to better identify patients with borderline and intermediate clinical risk who should initiate statin therapy.
Socioeconomic and Geographic Disparities in the Referral and Treatment of Pancreatic Cancer at High-Volume Centers
Authors: Thomas L. Sutton, Blake Beneville, Alicia J. Johnson, Skye C. Mayo, Erin W. Gilbert, Charles D. Lopez, Aaron J. Grossberg, Flavio G. Rocha, Brett C. Sheppard
Journal: JAMA Surgery (2022)

Treatment at high-volume centers (HVCs) has been associated with improved overall survival (OS) in patients with pancreatic ductal adenocarcinoma (PDAC); however, it is unclear how patterns of referral affect these findings.To understand the relative contributions of treatment site and selection bias in driving differences in outcomes in patients with PDAC and to characterize socioeconomic factors associated with referral to HVCs.A population-based retrospective review of the Oregon State Cancer Registry was performed from 1997 to 2019 with a median 4.3 months of follow-up. Study participants were all patients diagnosed with PDAC in Oregon from 1997 to 2018 (n = 8026).The primary exposures studied were diagnosis and treatment at HVCs (20 or more pancreatectomies for PDAC per year), low-volume centers ([LVCs] less than 20 per year), or both.OS and treatment patterns (eg, receipt of chemotherapy and primary site surgery) were evaluated with Kaplan-Meier analysis and logistic regression, respectively.Eight thousand twenty-six patients (male, 4142 [52%]; mean age, 71 years) were identified (n = 3419 locoregional, n = 4607 metastatic). Patients receiving first-course treatment at a combination of HVCs and LVCs demonstrated improved median OS for locoregional and metastatic disease (16.6 [95% CI, 15.3-17.9] and 6.1 [95% CI, 4.9-7.3] months, respectively) vs patients receiving HVC only (11.5 [95% CI, 10.7-12.3] and 3.9 [95% CI, 3.5-4.3] months, respectively) or LVC-only treatment (8.2 [95% CI, 7.7-8.7] and 2.1 [95% CI, 1.9-2.3] months, respectively; all P < .001). No differences existed in disease burden by volume status of diagnosing institution. When stratifying by site of diagnosis, HVC-associated improvements in median OS were smaller (locoregional: 10.4 [95% CI, 9.5-11.2] vs 9.9 [95% CI, 9.4-10.4] months; P = .03; metastatic: 3.6 vs 2.7 months, P < .001) than when stratifying by the volume status of treating centers, indicating selection bias during referral. A total of 94% (n = 1103) of patients diagnosed at an HVC received HVC treatment vs 18% (n = 985) of LVC diagnoses. Among patients diagnosed at LVCs, later year of diagnosis and higher estimated income were independently associated with higher odds of subsequent HVC treatment, while older age, metastatic disease, and farther distance from HVC were independently associated with lower odds.LVC-to-HVC referrals for PDAC experienced improved OS vs HVC- or LVC-only care. While disease-related features prompting referral may partially account for this finding, socioeconomic and geographic disparities in referral worsen OS for disadvantaged patients. Measures to improve access to HVCs are encouraged.
Performance of Cardiovascular Risk Prediction Models Among People Living With HIV
Authors: Cullen Soares, Michael Kwok, Kent-Andrew Boucher, Mohammed Haji, Justin B. Echouffo-Tcheugui, Christopher T. Longenecker, Gerald S. Bloomfield, David Ross, Eric Jutkowtiz, Jennifer L. Sullivan, James L. Rudolph, Wen-Chih Wu, Sebhat Erqou
Journal: JAMA Cardiology (2022)

Extant data on the performance of cardiovascular disease (CVD) risk score models in people living with HIV have not been synthesized. To synthesize available data on the performance of the various CVD risk scores in people living with HIV. PubMed and Embase were searched from inception through January 31, 2021. Selected studies (1) were chosen based on cohort design, (2) included adults with a diagnosis of HIV, (3) assessed CVD outcomes, and (4) had available data on a minimum of 1 CVD risk score. Relevant data related to study characteristics, CVD outcome, and risk prediction models were extracted in duplicate. Measures of calibration and discrimination are presented in tables and qualitatively summarized. Additionally, where possible, estimates of discrimination and calibration measures were combined and stratified by type of risk model. Measures of calibration and discrimination. Nine unique observational studies involving 75 304 people (weighted average age, 42 years; 59 490 male individuals [79%]) living with HIV were included. In the studies reporting these data, 86% were receiving antiretroviral therapy and had a weighted average CD4+ count of 449 cells/μL. Included in the study were current smokers (50%), patients with diabetes (5%), and patients with hypertension (25%). Ten risk prediction scores (6 in the general population and 4 in the HIV-specific population) were analyzed. Most risk scores had a moderate performance in discrimination (C statistic: 0.7-0.8), without a significant difference in performance between the risk scores of the general and HIV-specific populations. One of the HIV-specific risk models (Data Collection on Adverse Effects of Anti-HIV Drugs Cohort 2016) and 2 of the general population risk models (Framingham Risk Score [FRS] and Pooled Cohort Equation [PCE] 10 year) had the highest performance in discrimination. In general, models tended to underpredict CVD risk, except for FRS and PCE 10-year scores, which were better calibrated. There was substantial heterogeneity across the studies, with only a few studies contributing data for each risk score. Results of this systematic review and meta-analysis suggest that general population and HIV-specific CVD risk models had comparable, moderate discrimination ability in people living with HIV, with a general tendency to underpredict risk. These results reinforce the current recommendations provided by the American College of Cardiology/American Heart Association guidelines to consider HIV as a risk-enhancing factor when estimating CVD risk.
Liver RBFOX2 regulates cholesterol homeostasis via Scarb1 alternative splicing in mice
Authors: Helen A. B. Paterson, Sijia Yu, Natalia Artigas, Miguel A. Prado, Nejc Haberman, Yi-Fang Wang, Andrew M. Jobbins, Elena Pahita, Joao Mokochinski, Zoe Hall, Maryse Guerin, Joao A. Paulo, Soon Seng Ng, Francesc Villarroya, Sheikh Tamir Rashid, Wilfried Le Goff, Boris Lenhard, Inês Cebola, Daniel Finley, Steven P. Gygi, Christopher R. Sibley, Santiago Vernia
Journal: Nature Metabolism (2022)

Abstract RNA alternative splicing (AS) expands the regulatory potential of eukaryotic genomes. The mechanisms regulating liver-specific AS profiles and their contribution to liver function are poorly understood. Here, we identify a key role for the splicing factor RNA-binding Fox protein 2 (RBFOX2) in maintaining cholesterol homeostasis in a lipogenic environment in the liver. Using enhanced individual-nucleotide-resolution ultra-violet cross-linking and immunoprecipitation, we identify physiologically relevant targets of RBFOX2 in mouse liver, including the scavenger receptor class B type I ( Scarb1 ). RBFOX2 function is decreased in the liver in diet-induced obesity, causing a Scarb1 isoform switch and alteration of hepatocyte lipid homeostasis. Our findings demonstrate that specific AS programmes actively maintain liver physiology, and underlie the lipotoxic effects of obesogenic diets when dysregulated. Splice-switching oligonucleotides targeting this network alleviate obesity-induced inflammation in the liver and promote an anti-atherogenic lipoprotein profile in the blood, underscoring the potential of isoform-specific RNA therapeutics for treating metabolism-associated diseases.
Association of Biologic Treatment in Hidradenitis Suppurativa With Reduced Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio
Authors: Niamh Kearney, Collette McCourt, Roisin Hambly, Rosalind Hughes, Donal O’Kane, Brian Kirby
Journal: JAMA Dermatology (2022)

This cohort study assesses whether an association exists between biologic treatment for hidradenitis suppurativa and neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and monocyte-lymphocyte ratio.
Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity
Authors: Elena Kempf, Kathrin Landgraf, Robert Stein, Martha Hanschkow, Anja Hilbert, Rami Abou Jamra, Paula Boczki, Gunda Herberth, Andreas Kühnapfel, Yu-Hua Tseng, Claudia Stäubert, Torsten Schöneberg, Peter Kühnen, N. William Rayner, Eleftheria Zeggini, Wieland Kiess, Matthias Blüher, Antje Körner
Journal: Nature Metabolism (2022)

Here we report a heterozygous tandem duplication at the ASIP (agouti signaling protein) gene locus causing ubiquitous, ectopic ASIP expression in a female patient with extreme childhood obesity. The mutation places ASIP under control of the ubiquitously active itchy E3 ubiquitin protein ligase promoter, driving the generation of ASIP in patient-derived native and induced pluripotent stem cells for all germ layers and hypothalamic-like neurons. The patient's phenotype of early-onset obesity, overgrowth, red hair and hyperinsulinemia is concordant with that of mutant mice ubiquitously expressing the homolog nonagouti. ASIP represses melanocyte-stimulating hormone-mediated activation as a melanocortin receptor antagonist, which might affect eating behavior, energy expenditure, adipocyte differentiation and pigmentation, as observed in the index patient. As the type of mutation escapes standard genetic screening algorithms, we rescreened the Leipzig Childhood Obesity cohort of 1,745 patients and identified four additional patients with the identical mutation, ectopic ASIP expression and a similar phenotype. Taken together, our data indicate that ubiquitous ectopic ASIP expression is likely a monogenic cause of human obesity.
HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1
Authors: Fara Brasó-Maristany, Gaia Griguolo, Nuria Chic, Tomás Pascual, Laia Paré, Julia Maues, Patricia Galván, Maria Vittoria Dieci, Federica Miglietta, Tommaso Giarratano, Olga Martínez-Sáez, Mercedes Marín-Aguilera, Francesco Schettini, Benedetta Conte, Laura Angelats, Maria Vidal, Barbara Adamo, Montserrat Muñoz, Esther Sanfeliu, Blanca González, Ana Vivancos, Patricia Villagrasa, Joel S Parker, Charles M Perou, PierFranco Conte, Aleix Prat, Valentina Guarneri
Journal: JNCI Journal of the National Cancer Institute (2022)

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.
Two Steps Forward, One Step Back
Authors: Andreas H. Diacon
Journal: New England Journal of Medicine (2022)

Tuberculosis is an important cause of death worldwide, and drug resistance is implicated in one third of the almost 2 million deaths from tuberculosis each year.1 Previous regimens for drug-resistant tuberculosis took 18 to 24 months to complete. Patients disliked painful and inconvenient daily injections, and caregivers expressed despair about trying to enforce adherence to toxic and ineffective regimens. In time, revised guidelines allowed selected patients to receive treatment for only 9 months, but daily injections and poor overall success remained.1 Progress accelerated with the Food and Drug Administration approval in 2012 of bedaquiline, the first new antituberculosis agent in . . .